The goal of this project has been to design and synthesize molecules derived from gp120 of HIV that bind to the CD4 receptor in the same fashion as the intact gp120. By binding to CD4, the peptide-based molecules competitively block the binding of gp120 to CD4 and, therefore, infection of cells by HIV-1. The materials we have made will be developed further as antagonists of HIV binding for in vivo uses, for targeting drugs and other therapeutics to CD4-bearing cells and as components of HIV vaccines. In addition, the peptide-derived materials are used to study cellular events that result from the binding of a CD4-specific peptide to the cell. We have observed peptide-induced signal transduction in CD4- bearing cells and the resulting cellular events provide us with insight into the pathogenesis caused by the chronic exposure of host cells to gp120. The understanding of the processes may lead to an understanding of the molecular basis behind AIDS in which the numbers of CD4-bearing cells decrease over several years in HIV-infected individuals. A necessary property of the active peptides is that they contain helical conformations for the activity of binding CD4 and for blocking the interaction of gp120 to CD4. The peptides are 15 to 18 amino acids in length and directly compete with the virus to block infection of cells in vitro. The D-forms of the peptides work as well as the L-forms indicating that there is probably great versatility in the recognition of HIV for binding CD4. We have learned that the hydrophobic surfaces of the various molecules are probably responsible for binding to CD4 ; this region of the helix is highly conserved among all the different strains of HIV-1, HIV-2 and SIV. Thus, the challenge has been to make materials that have an exposed hydrophobic surface but do not aggregate. Peptide aggregation is a problem in the field of hydrophobic drug development and we have this problem here. In addition, albumin is well-known to bind hydrophobic materials and our additional challenge has been to make a material that will not bind albumin and will not aggregate but will be recognized by CD4. Certain nonionic detergents appear to stabilize the helical conformation of the active peptide(s) and this may lead to active antagonists that could be components of spermicides. Spermicides are composed of nontoxic, nonionic detergents, so this finding argues compellingly for the introduction of clinical trials which test our helical peptides as HIV blocking agents. The ability of an adjuvant to preserve the conformation of an active peptide has been studied. The results clearly indicate that the adjuvants containing oil-like molecules such as the paraffin oil found in Freund's adjuvant will destroy the helical conformation by interfering with hydrophobic forces holding the helices together. In doing so, the adjuvants themselves disrupt conformation-dependent antibody biosynthesis.